mRNA vaccine against malaria effective in preclinical model
Authors: Munyaradzi Makoni
Journal: The Lancet Microbe (2023)

An mRNA vaccine candidate that produces an immune response against malaria parasites in the liver has shown promise in a preclinical study in mice by Mitch Ganley and colleagues. Following a mosquito bite, Plasmodium spp sporozoites move through the host bloodstream to the liver, where the parasites mature into schizonts, a form that can infect red blood cells and cause symptomatic malaria. “[This blood stage] is responsible for the characteristic symptoms of malaria and is when the infected person can transmit malaria to a mosquito that bites them”, explains Paulo Bettencourt (Catholic University of Portugal, Lisbon, Portugal), who was not involved in the study. “Stopping the progression to the blood stage would prevent symptomatic malaria and break up the transmission cycle…for these reasons, liver stage malaria is considered by many as the bottleneck of the disease”. The vaccine candidate in the study by Ganley and colleagues was developed to specifically target this liver stage. In a collaborative effort, researchers from Australia, New Zealand, and Japan developed an mRNA-based vaccine that targets and stimulates protective immune cell responses against Plasmodium berghei in mice. Originally, the team had been investigating a novel target for malaria using peptide-based vaccines but, in 2018, shifted to investigating mRNA-based vaccines. Study co-author Lauren Holz (Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia) explains that the previous peptide-based vaccines were successful in protecting mice from liver-stage malaria but they could only contain a small protein fragment of a malaria protein, limiting their effectiveness. By contrast, mRNA vaccines can encode an entire malaria protein, which can induce a higher cellular immune response. The protein used in the latest study was ribosomal protein L6 (RPL6), which has been shown to have little structural variation in Plasmodium falciparum. “In this study, we produced and tested a novel mRNA vaccine platform designed to generate strong CD8 T-cell responses in the liver”, says Holz. “We found our vaccine was exceptional at generating a particular type of CD8 T cell in the liver called tissue-resident memory cells, and these cells could protect against malaria”. Prof William Heath (Doherty Institute for Infection and Immunity, University of Melbourne), another co-author, added: “The surprise was that by adding a novel chemical to a standard mRNA vaccine, we could instruct the immune system to make a powerful response in the liver, the part of the body where malaria parasites infect initially…this means that our vaccine can make extra strong immune responses in the liver that can kill malaria parasites before they come out into the blood and cause sickness; with more development, this vaccine may be about to prevent malaria in people”. The study shows that the vaccine candidate induced protection in 80% of the mice (n=15) when challenged with sporozoites, and that this protection against liver-stage malaria depends on liver-resident CD8 T cells. Futhermore, efficacy of the mRNA vaccine was not affected by pre-exposure to blood-stage parasites, which, according to Holz, is promising as it suggests the vaccine could have a protective effect in people in endemic areas who have previously had Plasmodium spp parasitaemia. “These results are exciting and promising”, says Bettencourt, “[but] the vaccine candidate fails to induce high levels of protection if the adjuvant is removed.” The adjuvant used in this study was α-galactosylceramide, a natural killer T-cell agonist that is enriched in the liver. “This [effect of adjuvant] can be observed in many other vaccines, where the efficacy is strongly linked to the adjuvant used,” Bettencourt explains. Heath also added that although the findings are promising, they are tempered by the fact that so far it has only been done in mice. “We need to take a number of steps to translate this into a human vaccine, which will take time and [require] more funding”, he says. Developing any vaccine against malaria, including an mRNA vaccine, has its challenges, the biggest, according to Bettencourt, being the identification of the optimal antigen or combination of antigens that can target multiple parasite life stages and species (ie, against both P falciparum and Plasmodium vivax) and elicit a long-lasting protective response in endemic populations and block transmission in endemic areas. An mRNA-based malaria vaccine would also need to be produced on a very large scale, and manufacturing and distribution of the vaccine could prove challenging due to specific requirements of mRNA vaccines that can limit their availability, such as their high production costs, cold-chain requirements, difficulties in delivering the vaccines to populations in remote locations, and the need for advance market purchasing. Therefore, programmes that improve access to new vaccines, such as Gavi, The Vaccine Alliance, will need to be involved to address these challenges. The next step, Holz says, is to start the transition of these vaccines from preclinical models to studies in people. More broadly, other researchers could use Ganley and colleagues’ results and modify their vaccine platform to target other liver infections such as hepatitis viruses.